Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.5.1.2 (DNA ligase)
 2,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymine-DNA glycosylase (TDG), a DNA repair enzyme specific for G/T mismatches, plays a role in the regulation of gene expression through its physical interaction with transcription factors. Here, we show that TDG functionally associates with members of the p53 tumor suppressor family and directly modulates their activity. Yeast two-hybrid analysis indicated a physical interaction between a region including the oligomerization domain (OD) of p73alpha (residues 345-380) or p53 (residues 319-360) and residues 123-346 of TDG, which localizes in the G/T glycosylase catalytic domain (residues 123-372). This interaction was also detected in vitro and in vivo by GST pull-down and immunoprecipitation assays, respectively. TDG over-expression promoted the p73- and p53-mediated transcriptional activation of the p21Waf1 promoter in a dose-dependent manner. Further, TDG enhanced the p53 or p73alpha-induced growth repression. These observations suggest that TDG modulates the biological function of p53 and other members of the p53 family as a transcriptional coactivator.
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PMID:Thymine-DNA glycosylase interacts with and functions as a coactivator of p53 family proteins. 1895 77

Thymine DNA glycosylase (TDG) is a member of the uracil DNA glycosylase (UDG) superfamily of DNA repair enzymes. Owing to its ability to excise thymine when mispaired with guanine, it was proposed to act against the mutability of 5-methylcytosine (5-mC) deamination in mammalian DNA. However, TDG was also found to interact with transcription factors, histone acetyltransferases and de novo DNA methyltransferases, and it has been associated with DNA demethylation in gene promoters following activation of transcription, altogether implicating an engagement in gene regulation rather than DNA repair. Here we use a mouse genetic approach to determine the biological function of this multifaceted DNA repair enzyme. We find that, unlike other DNA glycosylases, TDG is essential for embryonic development, and that this phenotype is associated with epigenetic aberrations affecting the expression of developmental genes. Fibroblasts derived from Tdg null embryos (mouse embryonic fibroblasts, MEFs) show impaired gene regulation, coincident with imbalanced histone modification and CpG methylation at promoters of affected genes. TDG associates with the promoters of such genes both in fibroblasts and in embryonic stem cells (ESCs), but epigenetic aberrations only appear upon cell lineage commitment. We show that TDG contributes to the maintenance of active and bivalent chromatin throughout cell differentiation, facilitating a proper assembly of chromatin-modifying complexes and initiating base excision repair to counter aberrant de novo methylation. We thus conclude that TDG-dependent DNA repair has evolved to provide epigenetic stability in lineage committed cells.
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PMID:Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. 2127 27

Thymine DNA glycosylase (TDG) performs essential functions in maintaining genetic integrity and epigenetic regulation, which also plays an essential role in DNA demethylation. In this work, the novel iridium(III) complex 1 with an anchor tail was synthesized and employed to construct a G-quadruplex-based assay for detecting TDG activity in aqueous solution by using the mismatched base excising property of TDG with T4 DNA ligase and phi29 DNA polymerase, in concert with the rolling circle amplification (RCA) strategy. The assay achieved a detection limit of 0.048UmL(-)(1) (0.012ngmL(-1)), and showed high selectivity towards TDG even in the presence of other proteins and enzymes. Additionally, the assay could function in diluted cellular debris.
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PMID:A G-quadruplex-selective luminescent probe with an anchor tail for the switch-on detection of thymine DNA glycosylase activity. 2749 8

Thymine DNA glycosylase (TDG) is a DNA repair enzyme that excises a variety of mismatched or damaged nucleotides (nts), e.g. dU, dT, 5fC and 5caC. TDG is shown to play essential roles in maintaining genome integrity and correctly programming epigenetic modifications through DNA demethylation. After locating the lesions, TDG employs a base-flipping strategy to recognize the damaged nucleobases, whereby the interrogated nt is extruded from the DNA helical stack and binds into the TDG active site. The dynamic mechanism of the base-flipping process at an atomistic resolution, however, remains elusive. Here, we employ the Markov State Model (MSM) constructed from extensive all-atom molecular dynamics (MD) simulations to reveal the complete base-flipping process for a G.T mispair at a tens of microsecond timescale. Our studies identify critical intermediates of the mispaired dT during its extrusion process and reveal the key TDG residues involved in the inter-state transitions. Notably, we find an active role of TDG in promoting the intrahelical nt eversion, sculpturing the DNA backbone, and penetrating into the DNA minor groove. Three additional TDG substrates, namely dU, 5fC, and 5caC, are further tested to evaluate the substituent effects of various chemical modifications of the pyrimidine ring on base-flipping dynamics.
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PMID:Base-flipping dynamics from an intrahelical to an extrahelical state exerted by thymine DNA glycosylase during DNA repair process. 2976 10